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Nature Communications Sep 2023The zoonotic Rift Valley fever virus (RVFV) can cause severe disease in humans and has pandemic potential, yet no approved vaccine or therapy exists. Here we describe a...
The zoonotic Rift Valley fever virus (RVFV) can cause severe disease in humans and has pandemic potential, yet no approved vaccine or therapy exists. Here we describe a dual-mechanism human monoclonal antibody (mAb) combination against RVFV that is effective at minimal doses in a lethal mouse model of infection. We structurally analyze and characterize the binding mode of a prototypical potent Gn domain-A-binding antibody that blocks attachment and of an antibody that inhibits infection by abrogating the fusion process as previously determined. Surprisingly, the Gn domain-A antibody does not directly block RVFV Gn interaction with the host receptor low density lipoprotein receptor-related protein 1 (LRP1) as determined by a competitive assay. This study identifies a rationally designed combination of human mAbs deserving of future investigation for use in humans against RVFV infection. Using a two-pronged mechanistic approach, we demonstrate the potent efficacy of a rationally designed combination mAb therapeutic.
Topics: Animals; Mice; Humans; Antibodies, Monoclonal; Rift Valley fever virus; Biological Assay; Disease Models, Animal; Low Density Lipoprotein Receptor-Related Protein-1
PubMed: 37704627
DOI: 10.1038/s41467-023-41171-3 -
Zhonghua Liu Xing Bing Xue Za Zhi =... Dec 2021Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease discovered in the 21 century. This disease has been reported in several... (Review)
Review
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease discovered in the 21 century. This disease has been reported in several Asian countries, including China, Japan, South Korea, Vietnam, and Myanmar. Until 2019, SFTS cases have been reported in 25 provinces in China, and most of them were rural residents from mountains and hilly regions. Most SFTS cases were sporadic but geographically concentrated, mainly in Henan, Shandong, Anhui, Hubei, Liaoning, Zhejiang, and Jiangsu provinces. SFTSV infection was transmitted predominantly by a tick bite and potentially through close contact with the patient's blood or body fluids. Fever, gastrointestinal symptoms, thrombocytopenia, and leukopenia were common initial manifestations, and multiple organ failure or even death could occur in severe cases. The reported cases of SFTS have been gradually increasing, and the case fatality rate has remained at a high level, posing a severe threat to public health in China. This paper reviewed the epidemiological features, risk factors for disease transmission, and the clinical characteristics of SFTS to gain further knowledge of the disease, guide the prevention and management, and help reduce the case fatality rate.
Topics: Bunyaviridae Infections; China; Fever; Humans; Phlebovirus; Severe Fever with Thrombocytopenia Syndrome; Thrombocytopenia
PubMed: 34954991
DOI: 10.3760/cma.j.cn112338-20210529-00439 -
The American Journal of Tropical... Feb 2020The genus is a diverse group of globally occurring viruses, including tick-, mosquito-, and sand fly-borne pathogens. Phleboviruses have historically been classified by...
The genus is a diverse group of globally occurring viruses, including tick-, mosquito-, and sand fly-borne pathogens. Phleboviruses have historically been classified by serological methods. However, molecular methods alone have been used to identify emergent novel and related strains in recent years. This makes reconciling the classification of historically and newly characterized viruses challenging. To address this in part, we describe the characterization of the genomes of the Frijoles and Chilibre species complex phleboviruses, and three unclassified phleboviruses isolated in the Americas: Caimito, Itaporanga, and Rio Grande viruses that had previously only been described at the serological level. With the exception of , the phleboviruses sequenced in this study are phylogenetically related to the current species , , or the Chagres antigenic complex. Unexpectedly, molecular and phylogenetic analysis suggests Chilibre and Caimito viruses are taxonomically related to the family . These viruses have a genomic architecture similar to peribunyaviruses and form monophyletic groups within the genus . Our data highlight the importance of reconciling serological and molecular taxonomic classification. In addition, we suggest the taxonomy of Chilibre and Caimito viruses should be revised.
Topics: Americas; Animals; Genome, Viral; Humans; Phlebovirus; Phylogeny
PubMed: 31802735
DOI: 10.4269/ajtmh.19-0717 -
Journal of Medical Virology Mar 2024Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne hemorrhagic fever disease with high fatality rate of 10%-20%. Vaccines or specific...
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne hemorrhagic fever disease with high fatality rate of 10%-20%. Vaccines or specific therapeutic measures remain lacking. Human interferon inducible transmembrane protein 3 (hIFITM3) is a broad-spectrum antiviral factor targeting viral entry. However, the antiviral activity of hIFITM3 against SFTS virus (SFTSV) and the functional mechanism of IFITM3 remains unclear. Here we demonstrate that endogenous IFITM3 provides protection against SFTSV infection and participates in the anti-SFTSV effect of type Ⅰ and Ⅲ interferons (IFNs). IFITM3 overexpression exhibits anti-SFTSV function by blocking Gn/Gc-mediated viral entry and fusion. Further studies showed that IFITM3 binds SFTSV Gc directly and its intramembrane domain (IMD) is responsible for this interaction and restriction of SFTSV entry. Mutation of two neighboring cysteines on IMD weakens IFITM3-Gc interaction and attenuates the antiviral activity of IFITM3, suggesting that IFITM3-Gc interaction may partly mediate the inhibition of SFTSV entry. Overall, our data demonstrate for the first time that hIFITM3 plays a critical role in the IFNs-mediated anti-SFTSV response, and uncover a novel mechanism of IFITM3 restriction of SFTSV infection, highlighting the potential of clinical intervention on SFTS disease.
Topics: Humans; Bunyaviridae Infections; Membrane Proteins; Phlebovirus; RNA-Binding Proteins; Severe Fever with Thrombocytopenia Syndrome; Viral Proteins; Virus Internalization; Antiviral Restriction Factors
PubMed: 38402626
DOI: 10.1002/jmv.29491 -
Frontiers in Immunology 2021The genus consists of seven tick-borne bunyaviruses, among which four are known to infect humans. , severe fever with thrombocytopenia syndrome virus (SFTSV), poses... (Review)
Review
The genus consists of seven tick-borne bunyaviruses, among which four are known to infect humans. , severe fever with thrombocytopenia syndrome virus (SFTSV), poses serious threats to public health worldwide. SFTSV is a tick-borne virus mainly reported in China, South Korea, and Japan with a mortality rate of up to 30%. To date, most immunology-related studies focused on the antagonistic role of SFTSV non-structural protein (NSs) in sequestering RIG-I-like-receptors (RLRs)-mediated type I interferon (IFN) induction and type I IFN mediated signaling pathway. It is still elusive whether the interaction of SFTSV and other conserved innate immune responses exists. As of now, no specific vaccines or therapeutics are approved for SFTSV prevention or treatments respectively, in part due to a lack of comprehensive understanding of the molecular interactions occurring between SFTSV and hosts. Hence, it is necessary to fully understand the host-virus interactions including antiviral responses and viral evasion mechanisms. In this review, we highlight the recent progress in understanding the pathogenesis of SFTS and speculate underlying novel mechanisms in response to SFTSV infection.
Topics: Asia, Southeastern; Autophagy; DEAD Box Protein 58; Asia, Eastern; Humans; Immune Evasion; Immunity, Innate; Interferon Type I; Pakistan; Phlebovirus; Pyroptosis; Receptors, Immunologic; Severe Fever with Thrombocytopenia Syndrome; Signal Transduction; Viral Nonstructural Proteins; Virus Replication
PubMed: 34122440
DOI: 10.3389/fimmu.2021.676861 -
EBioMedicine Jan 2024Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne pathogen that causes severe hemorrhagic fever in humans, but no FDA-approved specific...
BACKGROUND
Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne pathogen that causes severe hemorrhagic fever in humans, but no FDA-approved specific antivirals or vaccines are available to treat or prevent SFTS.
METHODS
The plasmids construction and transfection were performed to generate the recombinant SFTSV harboring the nanoluciferase gene (SFTSV-Nluc). Immunostaining plaque assay was performed to measure viral titers, and DNA electrophoresis and Sanger sequencing were performed to evaluate the genetic stability. Luciferase assay and quantitative RT-PCR were performed to evaluate the efficacy of antivirals in vitro. Bioluminescence imaging, titration of virus from excised organs, hematology, and histopathology and immunohistochemistry were performed to evaluate the efficacy of antivirals in vivo.
FINDINGS
SFTSV-Nluc exhibited high genetic stability and replication kinetics similar to those of wild-type virus (SFTSVwt), then a rapid high-throughput screening system for identifying inhibitors to treat SFTS was developed, and a nucleoside analog, 4-FlU, was identified to effectively inhibit SFTSV in vitro. SFTSV-Nluc mimicked the replication characteristics and localization of SFTSVwt in counterpart model mice. Bioluminescence imaging of SFTSV-Nluc allowed real-time visualization and quantification of SFTSV replication in the mice. 4-FlU was demonstrated to inhibit the replication of SFTSV with more efficiency than T-705 and without obvious adverse effect in vivo.
INTERPRETATION
The high-throughput screening system based on SFTSV-Nluc for use in vitro and in vivo revealed that a safe and effective antiviral nucleoside analog, 4-FlU, may be a basis for the strategic treatment of SFTSV and other bunyavirus infections, paving the way for the discovery of antivirals.
FUNDING
This work was supported by grants from the National Key Research and Development Plan of China (2021YFC2300700 to L. Zhang, 2022YFC2303300 to L. Zhang), Strategic Priority Research Program of Chinese Academy of Sciences (XDB0490000 to L. Zhang), National Natural Science Foundation of China (31970165 to L. Zhang, U22A20379 to G. Xiao), the Science and Technology Commission of Shanghai Municipality (21S11903100 to Y. Xie), Hubei Natural Science Foundation for Distinguished Young Scholars (2022CFA099 to L. Zhang).
Topics: Humans; Animals; Mice; Phlebovirus; Severe Fever with Thrombocytopenia Syndrome; Nucleosides; China; Antiviral Agents; Fever
PubMed: 38176215
DOI: 10.1016/j.ebiom.2023.104944 -
Virology Journal Nov 2022Tick-borne diseases (TBDs) are bacterial, viral, and parasitic diseases transmitted by ticks. Viral TBDs have increased in prevalence over the last decade with many new... (Review)
Review
Tick-borne diseases (TBDs) are bacterial, viral, and parasitic diseases transmitted by ticks. Viral TBDs have increased in prevalence over the last decade with many new pathogenic viruses being discovered. Doxycycline is often empirically prescribed by clinicians to treat symptomatic patients following tick bites due to suspicions of bacterial TBDs such as Rocky Mountain spotted fever, anaplasmosis, and ehrlichiosis. However, viral TBDs are included in the differential diagnosis if patients do not clinically improve following antibiotic therapy. Several viral TBDs present with dermatological manifestations. Recognizing the differences in clinical presentations of TBDs, particularly of newly emerging viral TBDs in the United States, can help physicians identify the viral TBD, and possibly rule out viral illnesses with different clinical presentations. Therefore, this review discusses clinical manifestations, with an emphasis on dermatologic manifestations of Heartland Virus, Bourbon Virus, Powassan Virus, Deer Tick Virus and Colorado Tick Fever Virus. KEY POINTS: Viral tick-borne diseases have increased in prevalence over the last decade and often have similar clinical manifestations to other tick-borne diseases, including bacterial infections. Here, we review the dermatologic manifestations of Heartland Virus (HRTV), Bourbon Virus (BRBV), Powassan Virus (POWV), Deer Tick Virus (DTV) and Colorado Tick Fever Virus (CTFV) that are important for clinicians.
Topics: Animals; Humans; United States; Tick-Borne Diseases; Phlebovirus; Doxycycline; Encephalitis Viruses, Tick-Borne; Bacteriophages; Ticks
PubMed: 36443864
DOI: 10.1186/s12985-022-01924-w -
EMBO Molecular Medicine Mar 2024Severe fever with thrombocytopenia syndrome (SFTS) is a life-threatening disease caused by a novel bunyavirus (SFTSV), mainly transmitted by ticks. With no effective...
Severe fever with thrombocytopenia syndrome (SFTS) is a life-threatening disease caused by a novel bunyavirus (SFTSV), mainly transmitted by ticks. With no effective therapies or vaccines available, understanding the disease's mechanisms is crucial. Recent studies found increased expression of programmed cell death-1 (PD-1) on dysfunctional T cells in SFTS patients. However, the role of the PD-1/programmed cell death-ligand 1 (PD-L1) pathway in SFTS progression remains unclear. We investigated PD-1 blockade as a potential therapeutic strategy against SFTSV replication. Our study analyzed clinical samples and performed in vitro experiments, revealing elevated PD-1/PD-L1 expression in various immune cells following SFTSV infection. An anti-PD-1 nanobody, NbP45, effectively inhibited SFTSV infection in peripheral blood mononuclear cells (PBMCs), potentially achieved through the mitigation of apoptosis and the augmentation of T lymphocyte proliferation. Intriguingly, subcutaneous administration of NbP45 showed superior efficacy compared to a licensed anti-PD-1 antibody in an SFTSV-infected humanized mouse model. These findings highlight the involvement of the PD-1/PD-L1 pathway during acute SFTSV infection and suggest its potential as a host target for immunotherapy interventions against SFTSV infection.
Topics: Animals; Humans; Mice; Bunyaviridae Infections; Phlebovirus; B7-H1 Antigen; Severe Fever with Thrombocytopenia Syndrome; Leukocytes, Mononuclear; Programmed Cell Death 1 Receptor
PubMed: 38366162
DOI: 10.1038/s44321-024-00026-0 -
The American Journal of Tropical... Dec 2023Severe fever with thrombocytopenia syndrome virus (SFTSV), Heartland virus (HRTV) and Guertu virus (GTV) belong to the severe fever with thrombocytopenia...
Severe fever with thrombocytopenia syndrome virus (SFTSV), Heartland virus (HRTV) and Guertu virus (GTV) belong to the severe fever with thrombocytopenia syndrome/Heartland group of genus Bandavirus in the family Phenuiviridae of order Bunyavirales. Severe fever with thrombocytopenia syndrome virus and HRTV, identified from ticks from Asia and America, respectively, are important pathogens causing severe febrile diseases in humans. Guertu virus, closely related to these two viruses, is a potential pathogen, but no confirmed infection has been identified. So far, human-derived neutralizing monoclonal antibodies (mAbs) against SFTSV have been identified as having a great potential to be developed as antivirals; however, there is still a lack of neutralizing mAbs to GTV and HRTV. In this study, five neutralizing the mAbs against GTV and HRTV were obtained by hybridoma screening technology, four of which (14B4, 14D8, and 20D4 derived from GTV, and 27C8 derived from HRTV) showed cross reactivity and neutralization to all three viruses, and one derived from HRTV (10D6) neutralized HRTV specifically. The possible mechanisms of mAbs cross neutralization among the three viruses are discussed by analyzing their glycoprotein (GP) sequences and structures. Generating these neutralizing mAbs provides important antiviral candidates against GTV, HRTV, and SFTSV despite their differential activities, and their protective effect could be further evaluated in virus-infected mice. Their differential neutralizing efficiency and specificity further suggested that the three viruses share common mechanisms on the basis of GP functioning, and that HRTV poses a unique mechanism that differs from the other viruses. These findings shed light on developing broad-spectrum antiviral strategies against bandaviruses and promoting an understanding of the bandavirus infection process.
Topics: Animals; Humans; Mice; Antibodies, Neutralizing; Phlebovirus; Antibodies, Monoclonal; Severe Fever with Thrombocytopenia Syndrome; Glycoproteins; RNA Viruses; Antiviral Agents
PubMed: 37931293
DOI: 10.4269/ajtmh.23-0073 -
PLoS Neglected Tropical Diseases Jun 2022Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease with high case fatality rate. Unfortunately, no vaccine or antiviral... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease with high case fatality rate. Unfortunately, no vaccine or antiviral specifically targeting SFTS virus (SFTSV) are available for the time being. Our objective was to investigate the association between clinical laboratory parameters and fatality of SFTS patients.
METHODS
The systematic review was conducted in accordance with The Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. We searched (from inception to 24th February 2022) Web of Science, PubMed, National Knowledge Infrastructure databases and Wan Fang Data for relevant researchers on SFTS. Studies were eligible if they reported on laboratory parameters of SFTS patients and were stratified by clinical outcomes. A modified version of Newcastle-Ottawa scale was used to evaluate the quality of included studies. Standardized mean difference (SMD) was used to evaluate the association between laboratory parameters and outcomes. The between-study heterogeneity was evaluated quantitatively by standard Chi-square and the index of heterogeneity (I2). Heterogeneity was explored by subgroup and sensitivity analyses, and univariable meta-regression. Publication bias was determined using funnel plots and Egger's test.
RESULTS
We identified 34 relevant studies, with over 3300 participants across three countries. The following factors were strongly (SMD>1 or SMD<-0.5) and significantly (P<0.05) associated mortality: thrombin time (TT) (SMD = 1.53), viral load (SMD = 1.47), activated partial-thromboplastin time (APTT) (SMD = 1.37), aspartate aminotransferase (AST) (SMD = 1.19), lactate dehydrogenase (LDH) (SMD = 1.13), platelet count (PLT) (SMD = -0.47), monocyte percentage (MON%) (SMD = -0.47), lymphocyte percentage (LYM%) (SMD = -0.46) and albumin (ALB) (SMD = -0.43). Alanine aminotransferase, AST, creatin phosphokinase, LDH, PLT, partial-thromboplastin time and viral load contributed to the risk of dying of SFTS patients in each subgroup analyses. Sensitivity analysis demonstrated that the results above were robust.
CONCLUSIONS/SIGNIFICANCE
The abnormal levels of viral load, PLT, coagulation function and liver function, significantly increase the risk of SFTS mortality, suggesting that SFTS patients with above symptoms call for special concern.
Topics: Antiviral Agents; Bunyaviridae Infections; Humans; Laboratories, Clinical; Phlebovirus; Severe Fever with Thrombocytopenia Syndrome; Thromboplastin; Viral Load
PubMed: 35714138
DOI: 10.1371/journal.pntd.0010489